We have induced fresh peripheral blood K/natural killer cells to lyse a variety of target cells by coating them with anti-Fc gamma receptor (anti-Fc gamma R) (CD16) antibody hetero-cross-linked with anti-target cell antibody. The cytotoxic cell mediating this activity is different, as judged by depletion studies, from the CD3+, CD8+ T cell which is targeted by anti-CD3 cross-linked to anti-target cell antibody. Targeted K cell activity from some donors is enhanced by exposure to interleukin 2 but not interferon-gamma; other donors exhibit high amounts of this activity without stimulation. Specificity of lysis mediated by targeted K cells is dictated by the specificity of the anti-target cell antibody within the heteroconjugate, and bystander cells are not lysed by targeted K cells. Hetero-cross-linked antibodies containing anti-histocompatibility leukocyte antigen class I instead of anti-Fc gamma R (CD16) do not promote lysis, suggesting that the bridging of the target cell to Fc gamma R on the K cell is required to activate the lytic process. Lysis mediated by targeted K cells is much less inhibitable by polymerized IgG than is classical antibody-dependent cellular cytotoxicity. Fresh human melanoma cells are lysed specifically by K cells coated with anti-Fc gamma R (CD16) cross-linked to the 96.5 anti-melanoma antibody. In vivo, targeted K cells prevent tumor growth at low effector to target ratios in Winn-type tumor neutralization assays. Targeted K cells may therefore provide a new immunotherapeutic approach for the destruction of detrimental cells, such as tumor and virally infected cells.

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